The mutationathon highlights the importance of reaching standardization in estimates of pedigree-based germline mutation rates

  1. Lucie A Bergeron  Is a corresponding author
  2. Søren Besenbacher
  3. Tychele Turner
  4. Cyril J Versoza
  5. Richard J Wang
  6. Alivia Lee Price
  7. Ellie Armstrong
  8. Meritxell Riera
  9. Jedidiah Carlson
  10. Hwei-yen Chen
  11. Matthew W Hahn
  12. Kelley Harris
  13. April Snøfrid Kleppe
  14. Elora H López-Nandam
  15. Priya Moorjani
  16. Susanne P Pfeifer
  17. George P Tiley
  18. Anne D Yoder
  19. Guojie Zhang
  20. Mikkel H Schierup  Is a corresponding author
  1. University of Copenhagen, Denmark
  2. Aarhus University, Denmark
  3. Washington University in St. Louis, United States
  4. Arizona State University, United States
  5. Indiana University, United States
  6. Stanford University, United States
  7. University of Washington, United States
  8. California Academy of Sciences, United States
  9. University of California, Berkeley, United States
  10. Duke University, United States

Abstract

In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various non-human species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and how to appropriately account for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a 'Mutationathon', a competition organized among five research labs to compare germline mutation rate estimates for a single pedigree of rhesus macaques. We report almost a two-fold variation in the final estimated rate among groups using different post-alignment processing, calling, and filtering criteria and provide details into the sources of variation across studies. Though the difference among estimates is not statistically significant, this discrepancy emphasizes the need for standardized methods in mutation rate estimations and the difficulty in comparing rates from different studies. Finally, this work aims to provide guidelines for computational and statistical benchmarks for future studies interested in identifying germline mutations from pedigrees.

Data availability

The sequences of the pedigree analyzed are available on NCBI under the accession numbers:SRR10426295;SRR10426294;SRR10426275;SRR10426264;SRR10426253;SRR10426291;SRR10426290;SRR10426256;SRR10426255.The PCR experiment and Sanger resequencing produced for this work are deposited on Genbank under the accession number MZ661796 - MZ662076. Supplementary table 4 describe the data.The scripts used by the participants of the Mutationathon are publically available on different github described in the manuscript.Figure 3, 4 and 5 can be reproduced with the data in Figure 3 - source data 1, Figure 4 - source data 1, and Figure 5 - source data 1 .

The following data sets were generated

Article and author information

Author details

  1. Lucie A Bergeron

    Department of Biology, University of Copenhagen, Copenhagen, Denmark
    For correspondence
    lucie.a.bergeron@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1877-1690
  2. Søren Besenbacher

    Department of Molecular Medicine (MOMA), Aarhus University, Aarhus N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1455-1738
  3. Tychele Turner

    Department of Genetics, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Cyril J Versoza

    Center for Evolution and Medicine, Arizona State University, Tempe, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Richard J Wang

    Department of Biology, Indiana University, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alivia Lee Price

    Department of Biology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  7. Ellie Armstrong

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7107-6318
  8. Meritxell Riera

    Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  9. Jedidiah Carlson

    Department of Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Hwei-yen Chen

    Department of Biology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  11. Matthew W Hahn

    Department of Biology, Indiana University, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5731-8808
  12. Kelley Harris

    Department of Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0302-2523
  13. April Snøfrid Kleppe

    Department of Molecular Medicine, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7866-3056
  14. Elora H López-Nandam

    California Academy of Sciences, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Priya Moorjani

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Susanne P Pfeifer

    School of Life Sciences, Arizona State University, Tempe, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1378-2913
  17. George P Tiley

    Department of Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0053-0207
  18. Anne D Yoder

    Department of Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Guojie Zhang

    Department of Biology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  20. Mikkel H Schierup

    Bioinformatics Research Center, Aarhus University, Aarhus, Denmark
    For correspondence
    mheide@birc.au.dk
    Competing interests
    The authors declare that no competing interests exist.

Funding

Carlsbergfondet (CF16-0663)

  • Guojie Zhang

US national science foundation CAREER (DEB-2045343)

  • Susanne P Pfeifer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Virginie Courtier-Orgogozo, Université Paris-Diderot CNRS, France

Version history

  1. Preprint posted: August 31, 2021 (view preprint)
  2. Received: September 2, 2021
  3. Accepted: January 11, 2022
  4. Accepted Manuscript published: January 12, 2022 (version 1)
  5. Version of Record published: February 10, 2022 (version 2)
  6. Version of Record updated: November 9, 2022 (version 3)

Copyright

© 2022, Bergeron et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,915
    views
  • 340
    downloads
  • 36
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Lucie A Bergeron
  2. Søren Besenbacher
  3. Tychele Turner
  4. Cyril J Versoza
  5. Richard J Wang
  6. Alivia Lee Price
  7. Ellie Armstrong
  8. Meritxell Riera
  9. Jedidiah Carlson
  10. Hwei-yen Chen
  11. Matthew W Hahn
  12. Kelley Harris
  13. April Snøfrid Kleppe
  14. Elora H López-Nandam
  15. Priya Moorjani
  16. Susanne P Pfeifer
  17. George P Tiley
  18. Anne D Yoder
  19. Guojie Zhang
  20. Mikkel H Schierup
(2022)
The mutationathon highlights the importance of reaching standardization in estimates of pedigree-based germline mutation rates
eLife 11:e73577.
https://doi.org/10.7554/eLife.73577

Share this article

https://doi.org/10.7554/eLife.73577

Further reading

    1. Ecology
    2. Evolutionary Biology
    Chunxiao Li, Tao Deng ... Shiqi Wang
    Research Article

    The long-trunked elephantids underwent a significant evolutionary stage characterized by an exceptionally elongated mandible. The initial elongation and subsequent regression of the long mandible, along with its co-evolution with the trunk, present an intriguing issue that remains incompletely understood. Through comparative functional and eco-morphological investigations, as well as feeding preference analysis, we reconstructed the feeding behavior of major groups of longirostrine elephantiforms. In the Platybelodon clade, the rapid evolutionary changes observed in the narial region, strongly correlated with mandible and tusk characteristics, suggest a crucial evolutionary transition where feeding function shifted from the mandible to the trunk, allowing proboscideans to expand their niches to more open regions. This functional shift further resulted in elephantids relying solely on their trunks for feeding. Our research provides insights into how unique environmental pressures shape the extreme evolution of organs, particularly in large mammals that developed various peculiar adaptations during the late Cenozoic global cooling trends.

    1. Evolutionary Biology
    Tian Yue, Yongbo Guo ... Bing Su
    Research Article

    Compared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence between Tibetans and Han, and Tibetans show decreased immune response and endoplasmic reticulum stress. Remarkably, we detected a sex-biased expression divergence, where the male-infant placentas show a greater between-population difference than the female-infant placentas. The umbilical cord plays a key role in the sex-biased expression divergence, which is associated with the higher birth weight of the male newborns of Tibetans. We also identified adaptive histological changes in the male-infant placentas of Tibetans, including larger umbilical artery wall and umbilical artery intima and media, and fewer syncytial knots. These findings provide valuable insights into the sex-biased adaptation of human populations, with significant implications for medical and genetic studies of human reproduction.